JAC Advance Access published online on August 7, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn298
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Original research |
Orally administered β-lactamase enzymes represent a novel strategy to prevent colonization by Clostridium difficile
1 Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA 2 Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA 3 Ipsat Therapies LtdTM, Helsinki Business and Science Park, Viikinkaari 4, FI-00790 Helsinki, Finland
Received 18 April 2008; returned 16 May 2008; revised 27 June 2008; accepted 30 June 2008
* Correspondence address. Louis Stokes Cleveland Veterans Affairs Medical Center, Infectious Diseases Section, 10701 East Boulevard, Cleveland, OH 44106, USA. Tel: +1-216-791-3800 ext. 4788; Fax: +1-216-231-3482; E-mail: stiefel{at}medscape.com
Objectives: Antibiotics that are excreted into the intestinal tract and that disrupt the indigenous microbiota may promote infection by Clostridium difficile. We previously demonstrated that oral administration of a proteolysis-resistant, recombinant class A β-lactamase inactivates ampicillin or piperacillin excreted into the small intestine during parenteral treatment. We hypothesized that oral administration of this β-lactamase in conjunction with parenteral ampicillin or piperacillin would preserve the colonic microbiota, thus preventing the overgrowth of and toxin production by C. difficile in mice.
Methods: Subcutaneous ampicillin, subcutaneous piperacillin or either of these plus oral β-lactamase or either of these plus tazobactam-inactivated oral β-lactamase were administered to mice 24 and 12 h prior to harvest of caecal contents. Contents were inoculated with one of four strains of C. difficile, and growth and toxin production were assessed after 24 h of incubation under anaerobic conditions. To assess changes in stool microbiota, denaturing gradient gel electrophoresis (DGGE) of PCR-amplified ribosomal RNA genes was performed.
Results: Mice treated with ampicillin, piperacillin or either of these plus tazobactam-inactivated oral β-lactamase developed high-density colonization with C. difficile, whereas those treated with ampicillin or piperacillin plus the β-lactamase did not. DGGE demonstrated that antibiotic treatment resulted in significant alteration of the indigenous stool microbiota, whereas antibiotic plus β-lactamase treatment did not.
Conclusions: Administration of oral recombinant β-lactamase preserved the colonic microbiota of mice during parenteral β-lactam antibiotic treatment and prevented the overgrowth of and toxin production by C. difficile in caecal contents. Oral β-lactamase therapy may represent a novel approach towards preventing C. difficile infections in healthcare settings.
Key Words: hospital infections , antibiotic-associated diarrhoea , infection control , intestinal flora , β-lactams
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